CN106632730A - Chitosan derivative with endosome escape function as well as preparation method and application thereof - Google Patents

Chitosan derivative with endosome escape function as well as preparation method and application thereof Download PDF

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CN106632730A
CN106632730A CN201710009548.6A CN201710009548A CN106632730A CN 106632730 A CN106632730 A CN 106632730A CN 201710009548 A CN201710009548 A CN 201710009548A CN 106632730 A CN106632730 A CN 106632730A
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chitosan
preparation
endosome
chitosan derivatives
endosome escape
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CN106632730B (en
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夏晓静
胡英
徐蓓华
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

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Abstract

The invention discloses a chitosan derivative with an endosome escape function as well as a preparation method and application thereof. The chemical structure of the derivative is shown by a formula I in the specification, wherein n is the polymerization degree of chitosan, m/n is the methyl substitution degree of imidazole, and k/n is the proportion of amino on the unit saccharide ring not substituted by hydroxyethyl. Compared with the prior art, an amphiphilic chitosan derivative is prepared by a simple synthesis way, and endosome escape is realized through a proton sponge effect. The obtained carrier material has certain drug loading ability and can help a drug realize the endosome escape function.

Description

A kind of chitosan derivatives with endosome escape function and preparation method thereof and Using
Technical field
The present invention relates to a kind of chitosan derivatives with endosome escape function and its preparation method and application, belong to Biological medicament field of material technology.
Background technology
Cancer has become in the world the frequently-occurring disease and common disease of serious threat human life and health.At present cancer is faced Bed therapeutic modality has drug therapy, radiotherapy and operative treatment, and wherein chemotherapy is occupied an leading position in treatment of cancer.But because changing Learn drug selectivity not strong, playing normal tissue organ when tumour cell, the breeding of suppression growth of tumour cell are acted on is killed And cell also plays same purpose, serious bad reaction is thereby produced, even result in chemotherapy failure.The nanometer of Recent study Though delivery system has tumor tissues targeting, can entering cell by pinocytosis approach, but inevitably swallowed for intension Body, ultimately forms lysosome and is degraded, so as to weaken the BA of medicine.Therefore, development can be by drug delivery extremely The carrier of target cell and the endosome escape function having is extremely urgent.
Shitosan (Chitosan) is the product of chitin deacetylation, is the polymeric alkali that nature is uniquely present in a large number Property glycosaminoglycan, the characteristic of its lotus positive electricity can interact with the proteoglycans of cell surface bear electricity, promote intracellular Gulp down intake.With synthesis macromolecular material compared with, with wide material sources, it is cheap, stable in properties, non-stimulated, without sensitization, without cause The advantages of mutation, good biocompatibility and biodegradability, low immunogenicity and inactive, this causes shitosan Have a wide range of applications in field of medicaments.
With a large amount of active aminos and hydroxyl in chitosan molecule chain, it is easy to chemical modification.The different synthesis condition of control And method, the chitosan derivatives with different qualities can be prepared.It is easy to be grafted various parents on the primary amino radical of chitosan molecule Oiliness small molecule, introduces hydrophobic grouping, that is, form the amphipathic chitose derivative with hydrophobic long-chain, can be certainly in water Send out and form nano-micelle, it has the features such as above-mentioned polymer micelle solubilization, Stability Analysis of Structures, long circulating and targeting.But such as Front described, the chitosan micelle targeting for carrying medicine does not ensure that stable performance drug effect into intracellular, also needs to experience endosome Phagocytosis so that be degraded.Therefore to enable medicine completely to enter cytoplasm, antineoplastic drug carrier should be made to possess endosome and is escaped Ease function.
The mechanism that endosome is escaped has four kinds：PH buffering effects (proton sponge effect), the pore effect of endosome film is interior Contain the photochemical cleavage of body film fusion effect and endosome film.Wherein endosome film pore effect is due to some polypeptides Matter has high-affinity with the hole on endosome film, and such as cationic amphiphilic polypeptide is combined with lipid bilayer, made in hole Tension force increase, amplification hole so as to realize from endosome escape.Film fusion is the endosome film knot caused by fusion protein Structure is disorderly and generation endosome is escaped, and such as haemoglutinin can be changed into hydrophobic under endosome condition of acidic pH from anionic hydrophilic consideration convey Helical form conformation, is conducive to film to merge.Photochemical cleavage to come from and there are light sensitive species on endosome and lysosome membrane, and it is in light According to lower induced synthesis oxygen radical so as to destroying membrane structure.Proton sponge effect is by can have high buffering under the conditions of protonation Ability and the reagent mediation generation for being easy to expand, wherein after the molecule rich in histidine is due to the imidazole ring protonation on histidine Buffering effect is shown, endosome film rupture can be caused.And for example there is protonation amido in PAMAM polymer architectures also to generate High buffering effect, improves the osmotic pressure of endosome, causes endosome film rupture.More than in four kinds of modes, sponge is protonated Effect mode is relative to be easier to realize, convenient use, advantage of lower cost, it is easy to combined with target ligands is easy to large-scale production.
At present, the research of existing endosome escape functional compounds is numerous, but there is also some problems, and such as effect is poor, Carry drug effect fruit poor etc..
The content of the invention
Goal of the invention：In order to solve above-mentioned technical problem, the invention provides a kind of shell with endosome escape function Polysaccharid derivative and its preparation method and application.
Technical scheme：In order to realize foregoing invention purpose, the invention discloses a kind of shell with endosome escape function Polysaccharid derivative, it is characterised in that its chemical structural formula is as shown in following formula I：
Wherein, n represents the degree of polymerization of shitosan, and m/n represents imidazolmethyl substitution value, and k/n represents the ammonia in unit sugar ring Base is not by the substituted ratio of ethoxy.
The n of 50kDa shitosans about 250 or so, 100kDa shitosans n about 500 or so；
When using 50kDa or 100kDa shitosans, k/n reflects one-step synthesis and reacts the non-grafted amino to ethoxy Replacement situation, is about between 0.831～1 according to experimental result k/n, i.e., k possible ranges are 207～250 or 415～500； M/n reflects imidazoles substitution value, is 0.189～0.205 according to experimental result, then the scope of m is 47～52, or 94～104.
Present invention also offers the preparation method of the chitosan derivatives, comprises the following steps：
(1) chitosan derivative makes amphipathic chitose -- hydroxyethyl chitosan (MHC)；
(2) synthesis of N- (4- imidazolmethyls)-hydroxyethyl chitosan (MHC)；
Reactions steps are as follows：
It is preferred that, the method for the step (1) is as follows：
Shitosan is dissolved in 10% acetum, is stirred to after being completely dissolved and is added 50% NaOH, heated up To 20-50 DEG C of reaction 6-12 hour, then it is on the rocks be cooled to 0-4 DEG C after add oxirane 2.5-10ml, be warming up to 40-60 DEG C it is anti- 12-18 hours are answered, room temperature is cooled to, the HCl for adding 5mol/L adjust pH to neutrality, and products therefrom Jing 3000rpm are centrifuged 10min, 0.8 μm of filtering with microporous membrane, dialysis is lyophilized to be obtained final product.
It is preferred that, the molecular weight of the shitosan is 50kDa or 100kDa.
It is preferred that, the method for the step (2) is as follows：
Take step (1) products therefrom and add water and be completely dissolved, plus appropriate 6%HAc is adjusted to PH=5 and adds 4- imidazole formaldehydes, and 80 DEG C of 12～24h of reaction are warming up to, appropriate 4mol/L NaOH are added after cooling to neutrality, and add 10% NaBH4, 5mol/L HCl is adjusted to neutrality, 0.8 μm of filtering with microporous membrane of Jing after centrifugation, and filtrate dialysis is lyophilized to be obtained final product.
The invention provides application of the chitosan derivatives in carrier micelle is prepared.
It is preferred that, the medicine in the carrier micelle is Quercetin or cumarin.
It is preferred that, adopt direct dissolution method, rotary evaporation, dialysis or emulsion process when preparing carrier micelle.
Technique effect：Relative to prior art, the present invention prepares amphipathic chitose and spreads out using simple synthesizing mean Biology, realizes that endosome is escaped by proton sponge effect.Resulting vehicle material has certain Drug loading capacity, helps medicine reality Existing endosome escape function.
Specific embodiment
The materials synthesis of embodiment 1
Material characterization method is as follows：Pass through1H NMR, organic element analysis carry out respectively taking for imidazolmethyl and ethoxy Determine for degree.Using the critical micelle concentration of pyrene fluorescence spectrum method for measuring MHC
1st, the synthesis of hydroxyethyl chitosan (HE-Cs)：1 gram of shitosan (50KDa 100KDa) is weighed, 10ml 2% is added HAc, stir to after being completely dissolved add 50% NaOH 10ml.It is warming up to 40 DEG C afterwards to react 12 hours, then cooling on the rocks Oxirane 10ml is added afterwards, is warming up to 50 DEG C of reaction 18h.Being cooled to room temperature adds 5mol/L HCl to adjust pH to neutrality.Gained Product Jing 3000rpm are centrifuged 10min, and 0.8 μm of filtering with microporous membrane, dialysis is freezed and obtained final product.
Elementary analysis understands different oxirane inventorys, can obtain different ethoxy substitution values.
Table 1：The relation of hydroxyethyl chitosan substitution value and oxirane inventory
Oxirane inventory Ethoxy substitution value
2.5mL 0.294～0.372
5.0mL 0.523～0.654
10.0mL 0.946～1.169
2nd, the synthesis of N- (4- imidazolmethyls)-hydroxyethyl chitosan (MHC)：Take above-mentioned product 0.6g plus 72ml water is completely molten Solution, plus in right amount 6%HAc is adjusted to PH=5 addition 0.14g 4- imidazole formaldehydes, and it is warming up to 80 DEG C of reaction 24h.It is after cooling plus appropriate 4mol/L NaOH to neutrality, and add 10% NaBH4,5mol/L HCl are adjusted to neutrality, 0.8 μm of miillpore filter of Jing after centrifugation Filter, filtrate dialysis is lyophilized to be obtained final product.
Pass through1H-NMR understands imidazolmethyl substitution value 0.189～0.205.
3rd, the critical micelle concentration of pyrene fluorescence spectrum method for measuring MHC is taken, compound concentration is 6 × 10-6The third of the pyrene of mol/L Ketone solution, precision measures 1mL and is placed in a series of 10mL volumetric flasks, and logical nitrogen stream flings to acetone, is separately added into the aqueous solution of MHC In right amount, and be diluted with water to scale make MHC concentration be respectively 0.2,0.4,1.0,4.0,10.0,20.0,50.0,100.0, 250.0、500.0、1000.0、2000.0、5000.0μg/mL.Above-mentioned solution ultrasound 30min, is placed in 65 DEG C of water-baths and is incubated 1h, Take out, dark place stands overnight under room temperature.The excitation spectrum of pyrene is drawn using fluophotometer, λ em=390nm are excited and launched Slit width is 3.0nm.Record the I of each solution excitation spectrum338/I333, with I338/I333The log concentration of MHC is mapped, meter Calculate CMC.
The inventory of table 2 is the critical micelle concentration of 10.0mL oxirane different molecular weight hydroxyethyl chitosans
Molecular weight CMC
HE-Cs(50KDa) 242.66μg/ml
HE-Cs(100KDa) 380.19μg/ml
Embodiment 2 carries medicine process optimization
With Quercetin as model drug, compare direct dissolution method, rotary evaporation, dialysis, emulsion process and prepare micella Drugloading rate is different.The Different solution (ethanol, dimethyl sulfoxide (DMSO), methyl alcohol) of Quercetin, carrier are compared using single factor exploration method dense Degree (1%, 0.67%, 0.5%) and medicine and carrier rate of charge (1:25、1:10、1:5) to the impact of drugloading rate, to carry medicine Measure carries out process optimization for index, makes and reaches certain density carrier micelle.As a result as shown in table 3 below and table 4.
The different preparation method gained carrier micelle drugloading rates of table 3
The single factor exploration process optimization result of table 4
The cellular uptake of embodiment 3 and intracellular endosome are escaped
Fluorescence probe with Coumarin-6 (C6) as hydrophobic drug, contains in micella, is carried out using laser co-focusing O＆A.
For ease of microexamination, MDA-MB-231 cells cultivate 24h with DMEM in 24 hole plates, and with micella 4h is incubated Afterwards, cell is flushed three times with PBS, and 4% paraformaldehyde is fixed.Nucleus Hoechst 33258 is dyeed before fluorescence is taken pictures, glue The cellular uptake of beam adopts fluorescence microscope.
CLSM is used to observe the internalization and endosome escape process of ensuing micella.MDA-MB-231 cells are in glass bottom Culture dish in cultivate 24h, respectively at 2h, 4h, 12h after C6-MHC micellas is added, cleaning three times is carried out with PBS, then use LysoTrackerTMRed is dyeed, and 4% paraformaldehyde is fixed, CLSM observations.
As a result show to be loaded into micella using hydrophobic fluorescence probe C6, observe MDA-MB-231 cell endocytic situations.C6 Micella experiment in vitro shows in 24h that burst size is less than 1%, illustrate in the cell it is observed that C6 major parts both be from C6 glue Beam is absorbed, rather than free C6.
Laser co-focusing experiment further demonstrate that the efficiency that micella is escaped from endosome.In MDA-MB-231 cells and C6 After micella (green fluorescence) incubation, endosome adopts LysoTrackerTMRed (red fluorescence) is dyeed.Into endosome micella Represented with yellow.After 2h incubations, hence it is evident that it was observed that intracellular yellow pixel, shows that most micella is all passed after cellular uptake It is progressive enter endosome.However, yellow fluorescence signal is considerably reduced in 4h, show that endosome escapes out micella.12h is observed Most weak red and green fluorescence, shows that C6 micellas efficiently escape from endosome.The red fluorescence of dyeing endosome exists Gradually decay.This destruction with cationic materials to the sour environment of endosome is relevant.
The cytotoxicity of embodiment 4
By mtt assay in the enterprising line blank micella of MDA-MB-231 cells, the cell toxicity test of carrier micelle.Biological material Material MTT analyses, by MDA-MB-231 cell incubations on 96 orifice plates, blank micella concentration is from 0.005 to 1000 μ g/mL, incubation 72h.The MTT tests of carrier micelle, are that the concentration of medicine is incubated into 72h from 0.001-10 μ g/mL.20uL MTT are added per hole (it is 5mg/mL to be dissolved in concentration in PBS) incubation 4h, adds 100uLDMSO to dissolve formazan crystallizations, and ELIASA is surveyed under 570nm Determine trap, by standard of untreated fish group data processing is carried out.
Mtt assay result shows that blank micella group is not observed obvious Apoptosis, illustrates the micella of blank without thin Cellular toxicity.The IC50 of carrier micelle is relatively low, illustrates that micella more effectively transmits medicine and produces cytotoxicity, plays effectively anti-swollen Knurl is acted on.

Claims (8)

1. a kind of chitosan derivatives with endosome escape function, it is characterised in that its chemical structural formula such as following formula I institute Show：
Wherein, n represents the degree of polymerization of shitosan, and m/n represents imidazolmethyl substitution value, and k/n represents amino in unit sugar ring not By the substituted ratio of ethoxy.
2. the preparation method of chitosan derivatives described in claim 1, it is characterised in that comprise the following steps：
(1) chitosan derivative makes amphipathic chitose -- hydroxyethyl chitosan (MHC)；
(2) synthesis of N- (4- imidazolmethyls)-hydroxyethyl chitosan (MHC)；
Reactions steps are as follows：
3. the preparation method of chitosan derivatives according to claim 2, it is characterised in that the method for the step (1) It is as follows：
Shitosan is dissolved in 10% acetum, is stirred to after being completely dissolved and is added 50% NaOH, be warming up to 20- 50 DEG C reaction 6-12 hours, then it is on the rocks be cooled to 0-4 DEG C after add oxirane 2.5-10ml, be warming up to 40-60 DEG C reaction 12- 18 hours, it is cooled to room temperature, the HCl for adding 5mol/L adjusts pH to neutrality, products therefrom Jing 3000rpm centrifugation 10min, 0.8 μm Filtering with microporous membrane, dialysis is lyophilized to be obtained final product.
4. the preparation method of chitosan derivatives according to claim 2, it is characterised in that the molecular weight of the shitosan For 50kDa or 100kDa.
5. the preparation method of chitosan derivatives according to claim 2, it is characterised in that the method for the step (2) It is as follows：
Take step (1) products therefrom and add water and be completely dissolved, plus appropriate 6%HAc is adjusted to PH=5 and adds 4- imidazole formaldehydes, and heat up To 80 DEG C of 12～24h of reaction, appropriate 4mol/L NaOH are added after cooling to neutrality, and add 10% NaBH4, 5mol/L HCl Neutrality is adjusted to, 0.8 μm of filtering with microporous membrane of Jing after centrifugation, filtrate dialysis is lyophilized to be obtained final product.
6. application of the chitosan derivatives described in claim 1 in carrier micelle is prepared.
7. application according to claim 6, it is characterised in that the medicine in the carrier micelle is Quercetin or tonka-bean Element.
8. application according to claim 6, it is characterised in that steamed using direct dissolution method, rotation when preparing carrier micelle Send out method, dialysis or emulsion process.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030129730A1 (en) * 2001-11-15 2003-07-10 Abdellatif Chenite Composition and method to homogeneously modify or cross-link chitosan under neutral conditions
CN105754017A (en) * 2016-03-11 2016-07-13 浙江医药高等专科学校 Preparation method of mannose-grafted trimethyl chitosan and application of preparation method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030129730A1 (en) * 2001-11-15 2003-07-10 Abdellatif Chenite Composition and method to homogeneously modify or cross-link chitosan under neutral conditions
CN105754017A (en) * 2016-03-11 2016-07-13 浙江医药高等专科学校 Preparation method of mannose-grafted trimethyl chitosan and application of preparation method

Non-Patent Citations (2)

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程萌萌等: "季铵化-N-(4-咪唑甲基)壳聚糖的制备及其胶束形成", 《化工进展》 *

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